PROJECT SUMMARY Immune biomarkers may be useful for early detection and prevention of colorectal cancer. However, very little is known about the potent immune pathway involving major histocompatibility complex (MHC) class I-like proteins in colorectal cancer. These proteins, expressed by gastrointestinal cells, serve as major ligands for natural killer cells. However, they may be cleaved from the cell surface and released into blood in a soluble form ? the mechanism widely used by tumors to escape from immune surveillance even at early stages of colorectal cancer development. In addition, MHC class I-like genes are highly polymorphic with functional mutations changing the secretion of these proteins into bloodstream and altering the binding between tumor and immune cells. These biological pathways provide opportunities for blood-based colorectal cancer screening and development of immune therapies aimed at the neutralization of MHC class I-like proteins in blood, although the utility of these proteins as clinical biomarkers in colorectal cancer remain to be determined. Our main hypothesis is that MHC class I-like proteins contribute to the risk of colorectal cancer development. To test this novel hypothesis, we propose to conduct a secondary data analysis in a prospective population- based study ? Atherosclerosis Risk in the Community cohort using existing information on six plasma MHC class I-like proteins measured three times over 20 years of follow-up, genotyping data in MHC class I-like genes and data about CRC and its risk factors. The use of existing data will allow for quick and cost efficient testing of our hypothesis. Understanding the role of MHC class I-like proteins in colorectal cancer is clinically important because inhibition of these proteins in blood would provide a novel opportunity for controlling colorectal tumor development and early detection. 1